Optimal management for alcoholic liver disease: Conventional medications, natural therapy or combination?

Table 1 The information of effects of current conventional medicines on the treatment of alcoholic liver disease

Medicine/compound	Type of model	Dosage/duration	Effects	Mechanisms	Ref.
Corticosteroid	RCT in severe AH	Prednisone (30 mg/d, 30 d)	Lower mortality AH group compared to antioxidant treated group		[37]
	RMT and double blind trials in severe AH	Methylprednisolone (32 mg within 7 d) and 28 d treatment and then tapered over 2 wk and discontinued	Decrease short-term mortality of patients with AH		[160]
Pentoxifylline	A double-blind, placebo-controlled trial	400 mg orally 3 times daily for 4 wk	Decrease in the risk of Progressing hepatorenal syndrome; Improve short-term survival in patients with AH		[42]
	A RCT followed by open study in severe AH patients	400 mg/d, orally for 4 wk and then tapered by 5 mg/wk for 7 wk	Better reduced mortality compared to prednisolone in AH		[161]
SAM	Ethanol-LPS-induced fibrotic rats	10 mg/kg bw, ip	Attenuate oxidative stress and HSC activation	Inhibition of TGF-β signaling pathway	[50]
	Double-blind, placebo-controlled trial in 220 patients with AH and cirrhosis	1600 mg/d orally	Decreased serum markers of cholestasis; Improved subjective symptoms such as pruritus, fatigue, and feeling of being unwell		[162]
PPAR-α agonists	C57BL/6J mice with ethanol (27.5% of total calories)	0.1% Wy-14643 for 4 wk	Decreased serum and hepatic fat accumulation	Enhancement of hepatic FA oxidation pathway; Increased PPAR-α mRNA expression by 5-fold	[163]
	C57BL/6J mice with 4 % ethanol (Ethanol feeding for 12 wk)	Wy-14643 (50 mg/kg per day) for last 2 wk	Decreased serum AST and ALT Dropped on score of hepatic steatosis and hepatocyte ballooning	Repress PI3K and COX-2 expression; Enhance adiponectin and HO-1; Increase SIRT1 protein expression	[164]
	C57BL/6J mice with ethanol containing diet (29% of total calories)	Rosiglitazone (3 mg/kg bw/d) for 2 wk	Reduced hepatic triglyceride content; Reduced AST and ALT	Upregulated level of adiponectin and its receptors; Enhance SIRT1-AMPK signaling pathway	[55]
Metformin	C57BL/6 mice TNF knockout mice PAI-1 knockout with ethanol (6 g/kg ig)	200 mg/kg ip for 4 d prior to ethanol administration	Reduced ALT; Prevented hepatic fat accumulation	Prevention of the upregulation of PAI-1	[57]
Metadoxine	HepG2, CFSC-2G and HSC treated with ethanol (50 mM) and acetaldehyde (175 µM)	10µg/mL for 24 h	Reduced peroxidation and oxidized GSH content	Decrease collagen secretion and IL-6, IL-8 and TNF-α secretion	[69]
Carvedilol	Male Wistar rats with ethanol (5%) fed	10 mg/kg per day for last 7 d of total 49 d	Reduced hepatic TG level and the accumulation of fatty droplets within hepatocytes;	Down-regulated FAS and SREBP-1, and up-regulated PPAR-α;	[56]
			Inhibited ethanol-induced the thickening of zone 3 vessel walls	Reduced the activation of HSCs with decrease induction of TGF-β1 and collagen
Propylthiouracil	Male Sprague-Dawley rat with ethanol consumption (36%)	50 mg/kg per day of Wy-14643 for last 2 wk for the last 5 d of 4-6 wk diets with alcohol	Increased hepatic blood flow; Reduces oxidative stress		[71]
Colchicine	RCT in 74 patients with cirrhosis	1 mg/d for 4.4 yr	Reduced serum N-terminal peptide of type III procollagen levels		[70]

AH: Alcoholic hepatitis; AMPK: 5’ adenosine monophosphate-activated protein kinase; ALT: Alanine transaminase; AST: Aspartate aminotransferase; bw: Body weight; COX-2: Cyclooxygenase-2, FA: Fatty acid; FAS: Fatty acid synthase; GSH: Glutathione; HepG2: Hepatoma G2 cell-line; HO-1: Heme oxygenase-1; HSC: Hepatic stellate cells; IL-6: Interleukin 6; IL-8: Interleukin-8; LPS: Lipopolysaccharide; mRNA: Messenger ribonucleic acid; P13K: Phosphoinositide 3-kinase; PAI-1: Plasminogen activator inhibiter-1; PPAR-α: Peroxisome proliferator-activated receptor-α; RCT: Randomized controlled trial; RMT: Respiratory muscle training; SIRT1: Sirtuin 1; SREBP1: Sterol regulator element binding protein 1; TG: Triglycerides; TGF-β: Tissue growth factor-β; TNF: Tumour necrosis factor; TNF-α: Tumour necrosis factor-α.

Table 2 The information of effects of current natural medicines on the treatment of alcoholic liver disease

Medicine/compound	Type of model	Dosage/duration	Effects	Mechanisms	Ref.
Vitamin E and C	Malnourished rats with ethanol	Vitamin E (15 mg/kg) Vitamin C (10 mg/kg); single and combined treatments	Decreased ethanol induced hepatic glutathione peroxidase activity and hepatic fibrosis; Attenuated the development of hepatomegaly and hepatic necroinflammation		[165]
Epigallocatechin-3-gallate (EGCG)	Male albino Wistar rats with Ethanol (6 g/kg per day) for 60 d	EGCG (100 mg/kg per day) for the last of 30 d of ethanol administration	Normalization of activities of enzymatic antioxidants; Reduction of lipid peroxidation		[93]
	Female Sprague-Dawley rats with ethanol (56%)	EGCG (100 mg/bw)	Partly blocked the gut leakiness; Reduced endotoxemia and lipid peroxidation	Blunted the elevated expressions of CD14, TNF-α, COX-2 and iNOS	[94]
	Male Wistar rats with ethanol for 5 wk	EGCG contained diet (3 g/L) for 2 wk and then ethanol-EGCG diet for 5 wk	Reduced serum AST and ALT	Enhancement of FA oxidation through increasing of CTP-1 and p-ACC expression	[95]
Silymarin (Silybum marianum)	RCT, double-blind, 170 patients with cirrhosis	140 mg/d for 3 times orally	Reduced the rate of mortality No side effect		[33]
	Alcohol induced baboons (50% of calories)	0.84 mg/calorie for 36 mo	Improve histologic stage of fibrosis	Decrease collagen I and (I) procollagen	[100]
	Alcohol and high fat induced rats	100 mg/kg per day, 150 mg/kg per day, 200 mg/kg per day for 6 wk	200 mg/kg per day decrease serum ALT and AST and hepatic fat contents	Attenuated NF-κB p65, ICAM-1 and IL-6 were found in silymarin groups (150 mg/kg, 200 mg)	[101]
Betaine	Ethanol diet Wistar rats	1% (w/v) in diet	Decrease hepatic ballooning and fat contents	Attenuate NOS production; Decrease CYP2E1 protein and activity	[106]
	High fat containing ethanol diet rats 6 g/kg for 8 more wk	200 and 400 mg/kg per day for 4 wk	Decrease ALT and AST	Inhibition of TLR-4 expression; Decrease serum endotoxin, TNF-α, IFN-γ and IL-18	[107]
Glycyrrhizin (Glycyrrhiza glabra)	Ethanol-CCl4 induced male SD rats	Intraperitoneal injections of potenlin (acquired from Hai Ning Pharmaceutical Co., Zhe Jiang, China)	Decreasing serum ALT levels	Normalized NF-κB binding activity	[114]
Ginsenosides	Ethanol-feeding mice Ethanol feeding hepatocytes (AML12 cell lines)	Red ginseng extract containing abundant ginsenosides (Rb1, Rb2, and Rd) (250 mg/kg or 500 mg/kg) for 4 wk in mice	Improves chronic alcohol-induced histopathological changes; Decreases in hepatic triglyceride content	Inhibition of lipogenesis pathway; Attenuated EtOH-induced cytochrome; P450 2E1, 4-hydroxynonenal, and nitrotyrosine levels; Activation of AMPK-SIRT1	[166]
	Alcohol consumption with high fat diet mice	Red ginseng (200 mg/kg per day) for last 2 wk	Lower ALT levels and no different AST	Reduced level of TNF-α and IL-1 and increase IL-10	[124]
Fenugreek seed polyphenol	EtOH (30 mM) induced Chang liver cells	20, 40, 60 mg/mL	Increased GSH/GSSG ratio Reduced EtOH-induced LDH leakage	Inhibition of NF-κB	[129]
	Ethanol induced rats (6 g/kg per day) for 30 d	200 mg/kg per day for 30 d	Improved lipid profile and reduced collagen content, crosslinking, aldehyde content and peroxidation		[132]
Curcumin	Alcohol (100 mM) induced rat primary hepatocytes	0-50 μmol/L	Ameliorated MDA and AST	Improved GSH and heme oxygenase-1 (HO-1) induction	[133]
	Alcohol-induced female Sprague-Dawley rats	400 mg/kg bw	Improved liver pathology, decreasing elevation of hepatic MDA	Suppressing of NF-κB activation	[134]
LIV-52	Ethanol-induced HepG2 cells (100 and 200 mM )	1% or 2% Liv.52 for 24 h		Normalized suppressed PPAR-α and induced TNF-α	[148]

ACC: Acetyl-CoA carboxylase; AML12: Alpha mouse liver 12; AMPK: 5’ adenosine monophosphate-activated protein kinase; ALT: Alanine transaminase; AST: Aspartate aminotransferase; bw: Body weight; CCL4: Chemokine ligand 4; CD14: Cluster of differentiation 14 gene; COX-2: Cyclooxygenase-2; CPT-1: Carnitine palmitoyl-transferase 1; CYP2E1: Cytochrome P450 2E1; EGCG: Epigallocatechin-3-gallate; etOH: Ethanol; FA: Fatty acid; GSH: Glutathione; GSSG: Glutathione disulfide; HepG2: Hepatoma G2 cell-line; HO-1: Heme oxygenase-1; ICAM-1: Intercellular adhesion molecule-1; IFN-γ: Interferon-γ; IL-1: Interleukin 1; IL-6: Interleukin 6; IL-10: Interleukin-10; IL-18: Interleukin-18; iNOS: Inducible nitric oxide synthase; LDH: Lactate dehydrogenase; MDA: Malondialdehyde; NF-κB: Nuclear factor kappa; NOS: Inducible nitric oxide synthase; RCT: Randomized controlled trial; SIRT1: Sirtuin-1; TLR-4: Toll-like receptor-4; TNF-α: Tumour necrosis factor-α.